Transcript Current issues in Antibiotic Use

Current issues in Antibiotic Use:
the Continued Evolution of
Antimicrobial Resistance
Bert K. Lopansri, MD
Division of Infectious Diseases and Clinical
Epidemiology
Associate Professor, University of Utah
Medical Director, Intermountain Central Laboratory
DISCLOSURES
• Research support from:
– Nanosphere, Inc.
– Ansell, Inc.
– Catheter Connections, Inc.
Objectives
• Discuss emerging issues related to
antimicrobial resistance
• Discuss methods to control antimicrobial
resistance
• Encourage healthcare workers to think about
how antibiotics are used
Fleming in reference to Penicillin
• The public will demand [the drug and]…then
will begin an era… of abuses. The microbes
are educated to resist penicillin and a host of
penicillin-fast organisms is bred out which can
be passed to other individuals…In such a case
the thoughtless person playing with penicillin
treatment is morally responsible for the death
of the man who finally succumbs to infection
with penicillin-resistant organism. I hope the
evil can be averted.
Fleming A. Penicillin’s finder assays its future. New York Times. 1945; 21
Outpatient antibiotic prescriptions
per 1000 Persons, 2010
LA Hicks. NEJM. 368;15. April 11, 2013
Trends in outpatient antibiotic use
in U.S. (per 1000 persons)
AGENT
1999
2010
% Change
2010 (UT)
ALL CLASSES
966
801
-17
791
Penicillins
352
248
-30
293
Macrolides
209
211
NC
176
Cephalosporins
117
114
-35
129
Fluoroquinolones
83
94
+14
69
Tetracyclines
71
67
73
TMP/Sulfa
74
66
51
0.33
1.0
Other (vanco, linezolid,
dapto, polymyxins,
carbapenems)
+200
0.7
Data from www.cddep.org (Center for Disease Dynamics, Economics & Policy)
Outpatient ABX Use: US vs. Sweden
U.S.
(2010)
ABX/1000 persons
833
TOP ANTIBIOTICS AZITHROMYCIN
PENICILLINS
SWEDEN
(2012)
388
PCN VK
DOXYCYCLINE
FLOXACILLIN
PIVMECILLINAM
NITROFURANTOIN
LA Hicks. NEJM. 368;15. April 11, 2013
A Ternhag. NEJM. 369;12. Sept 19, 2013
CASE #1
• 76 y/o man presented to ED with abrupt onset
of chills, nausea, vomiting, dysuria and
difficulty urinating.
• In usual state of health prior to admission.
• Other than constipation, ROS negative
• No hospitalizations in past 12 months
CASE #1
• PMHx:
–
–
–
–
DM
Recurrent DVT
HTN
Factor V Leiden
Deficiency
• MEDICATIONS (HOME):
–
–
–
–
–
–
Glipizide
Metformin
Lipitor
Coumadin
Lisinopril/HCTZ
Diltiazem
• SOCIAL HISTORY:
– Retired landscaper
– No ETOH, Illicits, Tobacco
– Exercises weekly
CASE #1
• VITALS: Temp 39.2, HR
108, BP 111/52, Sat
92%
• ABDOMEN:
Soft/slightly
distended/non-tender
• BACK: No CVA
tenderness
• LABS:
– Cr 1.41 (Baseline
1.25)
– WBC 3.7, HGB 14.2,
PLT 85
– Urinalysis: Cloudy,
Large Leuk
Esterase, >30 WBC
Question #1
• Patient was diagnosed with urosepsis. What
antibiotic regimen would you start?
a)
b)
c)
d)
e)
f)
Cefepime
Ceftriaxone
Imipenem or meropenem
Ertapenem
Ciprofloxacin
Piperacillin/Tazobactam
CASE #2
• 79 y/o woman with HPV, cirrhosis, DM
admitted with fever and diarrhea.
• Multiple episodes of daily, non-bloody
diarrhea and abdominal pain x 1 month.
• 1 week PTA, developed regular fevers to 101
• +urinary frequency without dysuria or
urgency.
• Recently returned from a 3 month stay in India
CASE #2
• PMHX
– Breast CA s/p lumpectomy
4/2013. On tamoxifen.
– DM
– HTN
– Hep B with cirrhosis
– Choledocholithiasis
• PSHX
– Lumpectomy
– Cholecystectomy
– R TKA
• EXAM:
– Temp 38.4, RR 25, HR 120,
BP 138/71
– Non-toxic
– ABD distended with diffuse
tenderness. Liver and
spleen unable to be
palpated
• LABS:
– WBC 13.0 (PMN 81.4%),
HGB 8.2, PLT 275
– BUN 36, Cr 3.17
– Urine: Cloudy, + Nitrite,
Large Leuk Esterase, >30
WBC
QUESTION #2
Patient was diagnosed with urosepsis. What antibiotic
regimen would you start?
a)
b)
c)
d)
e)
f)
Cefepime
Ceftriaxone
Imipenem/meropenem
Ertapenem
Ciprofloxacin
Piperacillin/Tazobactam
Hospital Course
• Blood + urine cultures:
for ESBL E. coli
• Case #1
– Started on Cefepime
– Switched to
MEROPENEM on Day #3
of hospitalization
• Case #2
– Started on Ciprofloxacin
and ceftriaxone
– Switched to
MEROPENEM on Day #3
E coli susceptibilities: CASE #1
AND #2
Susceptible Carbepenems
Nitrofurantoin
Resistant
All cephalosporins
Pip/Tazobactam
Cipro/levaquin
Amox/Clav
Ampicillin
Tobramycin
Gentamicin
Bactrim
QUESTION #3
• Carbapenem-resistant Enterobacteriaceae (CRE)
is:
a) An overhyped, story that is unlikely to be a
significant problem where I practice medicine.
b) A global problem
c) A U.S. problem
d) A problem only in certain parts of the world
e) Europe’s fault
f) What in the world is a CRE?
Emerging Antibiotic Resistant
Organisms
PCN Res
Strep
pneumo
VRE
MRSA
Penicillin
resistant
Staph
aureus
CRE
MDRO
P. aerug
FQR
CRAB
ESBL
E. coli
FQR Ceftriaxone FQR
Campy
NG Resistant
NG
FQR= fluoroquinolone resistant
MDRO=multidrug resistant
MRSA=methicillin resistant Staph aureus
NG=Neiserria gonorrhea
PCN=penicillin
CRAB=carbapenem resistant Acinetobacter baumanii
CRE=carbapenem resistant Enterobacteriaceae
ESBL=extended spectrum β-lactamase
VRE=vancomycin resistant Enterococcus
http://wellcommons.com/users/jestevens/photos/2011/apr/10/211822/
Fluorquinolone-resistant E. coli (%)
RESISTANT (2009)
Iceland
UK
US Mountain Region=18%
United States
Germany
Spain
Turkey
0%
10%
20%
30%
40%
50%
60%
http://www.cddep.org/ResistanceMap/bugdrug/EC-FQ#.Ui0G-Ra3CRI
Mechanisms of FQ Resistance
• Alterations in target enzymes
– DNA gyrase (GyrA and GyrB)
– Topoisomerase IV (ParC and ParE)
• Alterations in permeation of drug to reach
target
– Porin reduction
– Eflux pumps
Plasmid Mediated FQ Resistance
• Discovered in 1994
• Plasmid = pMG252
– Encodes QnrA protein
– Carries multiple resistance determinants
• Binds to DNA gyrase and Topoisomerase IV
• May be carried with other resistance genes
Risk Factors for Acquisition of FQ
Resistance in LTCF
• Prospective, cohort study
• 47.5% LTCF residents became colonized
• Time to colonization=57 days
Fecal Incontinence
Receipt of amox/clavulanate
Presence of urinary catheter
HR
1.78
6.48
3.81
95% CI
1.04, 3.06
1.43, 29.4
1.06, 13.8
JH Han, JID. 2013 Aug 28
Risk Factors for Acquisition of
Community-Acquired FQREC
• Nested case-control study
– FQREC=51, Controls=369
• Resistance to multiple antibiotics present
HR
2.03
95% CI
0.96-4.31
Receipt of FQ
17.5
6.0-50.7
Presence of urinary catheter
3.14
0.85-11.6
Hospitalization within previous 6
months
WE van der Starre. JAC. 2011;66 650-656
Number of β-lactamase enzymes
described during age of antibiotics
Number of Unique Enzymes
900
1973
2013
Julian Davies. Micro biol and Molecular Bio Rev. Sept. 2010, p. 417-433
• Enzymes that mediate resistance to extendedspectrum cephalosporins (third generation) and
monobactams but do not affect cephamycins
(cefoxitin/cefotetan) or carbapenems.
• Activity is reversed by clavulanic acid
Antibiotic Resistance Threats in the U.S., 2013. CDC
Location of gene
Inhibited by
clavulanic acid
Cefepime useful
Cephamycin
resistant
Pathogens
ESBL (CLASS A)
AmpC (CLASS C)
Plasmid
YES
Chromosomal
NO
NO
NO
YES
YES
Klebsiella pneumoniae
Escherichia coli
Proteus mirabilis
Enterobacter cloacae
Salmonella
E. cloacae
S. marcescens
C. freundii
M. Morgagnii
P. Aeruginosa
Y. Enterocolitica
Hafnia alvei
Common ESBLs
blaTEM/blaSHV
Epidemiology
blaCTX-M
Associated with HAIs Community-associated
infections
Preferential
targets
Number of
types
Ceftazidime
Cefotaxime
>100
>50
Distribution
Global
Global
Risk Factors for ESBL Infections
•
•
•
•
•
•
Length of hospital stay
Severity of illness
Time in ICU
Mechanical ventilation
Urinary catheterization
Previous antibiotic exposure
Bradford PA. Clin Microbiol Rev. 2001;14:933-951
M. McKenna. Nature. Vol 499. 25 July 2013
MECHANISMS OF CARBAPENEM
RESISTANCE
•
•
•
•
ESBL or AmpC with porin loss
Efflux pump
Carbapenemase
Common organisms
– Pseudomonas aeruginosa
– Acinetobacter spp.
– Enterobacteriaceae
CRE = Enterobacteriaceae resistant to one of the
carbepenems (Doripenem, imipenem or
meropenem) and third generation cephalosporins
(ceftriaxone, cefotaxime, ceftazidime)
Guidance for Control of Carbapenem-resistant Enterobacteriaceae –
2012 CRE Toolkit, CDC.
Antibiotic Resistance Threats in the U.S., 2013. CDC
Carbapenemases
Ambler
Classification
Class A
Enzyme
KPC, SME, IMI,
Organisms
Enterobacteriaceae
NMC, GES
Class B
(metallo-βlactamase)
NDM-1, IMP, VIM
Class D
OXA
Enterobacteriaceae,
Acinetobacter sp, P.
aeruginosa
Acinetobacter sp
Emergence of carbapenem
resistant Enterobacteriaceae
M. McKenna. Nature. Vol 499. 25 July 2013
Global Distribution of Klebsiella
pneumoniae carbapenemase
LS Munoz-Price. LANCET INFECT DISEASES. Vol 13:785. Sept 2013.
Regional spread of KPC CRE
1. DELAYED RECOGNITION OF KPC
2. AMPLIFICATION IN LTACHS AND NH
3. DESPITE INVOLVEMENT OF A SINGLE
LTACH, KPC QUICKLY BECAME A
REGIONAL PROBLEM
4. COORDINATED, REGIONAL EFFORTS
AMONG HOSPITALS, LTACHS, AND
PUBLIC HEALTH DEPT
S.Y. Won. CID. 2011;53(6):532-540
From www.medicaltourismmag.com
Outbreak of NDM-1 K. pneumo in Denver,
CO
• 8 cases between Jan-Oct 2012 at acute care
hospital
– 3 infections
– 5 identified by active surveillance
• K pneumoniae
– Susceptible to tigecycline with colisitin MIC≤2 μg/mL
– Highly related by PFGE
• Multiple transmission events in 3 units
• Not all patients overlapped
• Source not identified
MMWR. Feb. 15, 2013. 62(06);108
Antibiotic Susceptibilities for NDM-1
UK (n=37)
Chennai (n=44)
Haryana (n=26)
Imipenem
0%
0%
0%
Meropenem
3%
3%
3%
Piperacillin-tazobactam
0%
0%
0%
Cefotaxime
0%
0%
0%
Ceftazidime
0%
0%
0%
Cefpirome
0%
0%
0%
Aztreonam
11%
0%
8%
Ciprofloxacin
8%
8%
8%
Gentamicin
3%
3%
3%
Tobramycin
0%
0%
0%
Amikacin
0%
0%
0%
Minocycline
0%
0%
0%
Tigecycline
64%
56%
67%
Colistin
89%
94%
100%
KK Kumarasamy. Lancet ID. Vol 10. September 2010
Why are CREs clinically important?
KPC
Gene Location
NDM-1
Highly transferable plasmids
Treatment options
Outcomes
Limited
Infections associated with high mortality
Reporting required in Utah
Outbreaks
Mostly clonal
Mostly polyclonal
Asymptomatic carriage plays an key role
in transmission
Seven Ways to Preserve Antibiotics
•
•
•
•
•
•
•
US database for antibiotic use and resistance
Restrict use of antibiotics in agriculture
Prevent selected nosocomial infections
Practice antimicrobial stewardship
Promote use of new diagnostic tests (POC)
Reduce FDA antibiotic barrier
Facilitate public-private partnerships for
antibiotic development
Bartlett, JG. CID. 2013:56 (15 May)
CDC’s Four Core Actions
•
•
•
•
Prevent infections, prevent spread
Track resistance patterns
Improve use of antibiotics
Develop new antibiotics and diagnostic tests
Antibiotic Resistance Threats in the U.S., 2013. CDC
Mechanism of Resistance:
Horizontal Gene Transfer
INFECTION CONTROL MEASURES TO
PREVENT SPREAD OF CRE
• Awareness
• HAND HYGIENE
• Use glove and gowns
for every encounter
• Use equipment
dedicated
• Communicate with
facilities for transfers
• Limit HCW exposure
“Emerging Antibiotics”
Antibiotic Pipeline
PRODUCT
STATUS
WT P aerug
ESBL
KPC
NDM-1
Ceftolozane/taxobactama
Phase 3
Y
Y
N
N
Ceftazidime-avibactama
Phase 3
Y
Y
Y
N
Ceftaroline-avibactama
Phase 2
N
Y
Y
N
Imipenem/MK-7655a
Phase 2
Y
Y
Y
N
Plazomicinb
Phase 2
N
Y
Y
?
Eravacyclinec
Phase 2
N
Y
Y
?
Brilacidind
Phase 3
?
Y
?
?
a.
b.
c.
d.
Β-lactamase inhibitor
Aminoglycoside
Fluorocycline (targets ribosome)
Peptide defense protein mimetic
WT=wild type
ESBL=Extended spectrum beta lactamase
KPC=Klebsiella pneumoniae carbapenemase
NDM-1=New Delhi metallo-β-lactamase
HW Boucher. CID. 2013;56(12):1685-94
FDA approved rapid diagnostic platforms
Method
ADVANTAGES
DISADVANTAGES
MALDI-TOF
Mass spectrometry
Rapid speciation of microorganisms
Requires growth in
solid media
No resistance
markers
PNA FISH
Quick FISH
Nucleic acid
hybridization
Rapid speciation of
Staphylococcus sp,
Enterococcus sp, GNR, Candida
sp directly out of blood
culture
No resistance
markers
Microarray-based
nucleic acid
hybridization
Rapid speciation of most
common gram positive cocci
and resistance markers (mecA,
Van A, Van B) directly out of
blood culture
No gram negatives
rods or Candida sp
yet
Multiplex PCR
Gram positive, gram negative,
yeast, resistance markers
(VanA, Van B, mecA) directly
out of blood culture
No gram negative
resistance markers
Verigene BCGP
Film Array
BCID panel
SUMMARY
• Antibiotic resistance in gram negative
organisms is increasing rapidly
• Preventing spread of organisms in healthcare
settings is critical
• We need to be wiser about how we use
antibiotics
• While essential, waiting for new antibiotics is
not the solution for combating antibiotic
resistance
THANK YOU FOR YOUR
ATTENTION!